Pathogenesis of Type 2 Diabetes Mellitus

Carolina Solis-Herrera; Curtis Triplitt; Eugenio Cersosimo; Ralph A. DeFronzo

Pathogenesis of Type 2 Diabetes Mellitus

Review

In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000.

2021 Sep 27.

Authors

Carolina Solis-Herrera¹, Curtis Triplitt², Eugenio Cersosimo³, Ralph A. DeFronzo⁴

Book Editors

Kenneth R Feingold¹, Bradley Anawalt², Marc R Blackman³, Alison Boyce⁴, George Chrousos⁵, Emiliano Corpas⁶, Wouter W de Herder⁷, Ketan Dhatariya⁸, Kathleen Dungan⁹, Johannes Hofland¹⁰, Sanjay Kalra¹¹, Gregory Kaltsas¹², Nitin Kapoor¹³, Christian Koch¹⁴, Peter Kopp¹⁵, Márta Korbonits¹⁶, Christopher S Kovacs¹⁷, Wendy Kuohung¹⁸, Blandine Laferrère¹⁹, Miles Levy²⁰, Elizabeth A McGee²¹, Robert McLachlan²², Maria New²³, Jonathan Purnell²⁴, Rakesh Sahay²⁵, Amy S Shah²⁶, Frederick Singer²⁷, Mark A Sperling²⁸, Constantine A Stratakis²⁹, Dace L Trence³⁰, Don P Wilson³¹

Affiliations

¹ Assistant Professor, Department of Medicine, Division of Diabetes, UTHSCSA, Mail Code 7886, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
² Clinical Associate Professor of Medicine, Department of Medicine, Division of Diabetes, UTHSCSA, Mail Code 7886 – 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
³ Professor of Medicine, Department of Medicine, Division of Diabetes, UTHSCSA, Mail Code 7886 - 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
⁴ Professor of Medicine and Chair, Division of Diabetes, Department of Medicine, UTHSCSA, Mail Code 7886 - 7703 Floyd Curl Drive, San Antonio, TX 78229-3900

Book Affiliations

¹ Professor of Medicine Emeritus, University of California, San Francisco, CA
² Chief of Medicine at the University of Washington Medical Center and Professor and Vice Chair of the Department of Medicine, University of Washington
³ Sr. Physician Scientist, Washington DC VA Medical Center; Professor of Medicine & Rehabilitation Medicine, Georgetown University; Clinical Professor of Medicine, Biochemistry and Molecular Medicine, George Washington University; and Professor of Medicine (Part-time), Johns Hopkins University
⁴ Pediatric Endocrinologist and Associate Research Physician in the Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health
⁵ Professor of Pediatrics and Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
⁶ M.D. Ph.D in Gerontology. Honorary Professor of Medicine, Universidad de Alcalá, Madrid. Consultant in Endocrinology, Hospital HLA Guadalajara (Spain).
⁷ Professor of Endocrine Oncology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
⁸ Consultant in Diabetes, Endocrinology and General Medicine, Norfolk and Norwich University Hospitals NHS Foundation Trust and University of East Anglia, Norwich, UK.
⁹ Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Ohio State University
¹⁰ Consultant Endocrinologist, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, the Netherlands
¹¹ Consultant Endocrinologist, Department of Endocrinology, Bharti Hospital, Karnal, India
¹² Professor of General Medicine-Endocrinology, 1st Department of Propaedeutic Medicine, National and Kapodistrian University of Athens, Athens, Greece
¹³ Professor of Endocrinology, Department of Endocrinology, Diabetes and Metabolism, Christian Medical College & Hospital, Vellore, Tamil Nadu, India, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Australia.
¹⁴ Professor, The University of Tennessee Health Science Center, Memphis, Tennessee
¹⁵ Professor of Medicine and Chief of the Division of Endocrinology, Diabetology and Metabolism, University of Lausanne, Switzerland
¹⁶ Professor of Endocrinology and Metabolism, Centre Lead for Endocrinology and Deputy Institute Director, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, England
¹⁷ University Research Professor and Professor of Medicine (Endocrinology and Metabolism), Obstetrics & Gynecology, and BioMedical Sciences, at Memorial University of Newfoundland in St. John’s, Newfoundland, Canada.
¹⁸ Director of the Division of Reproductive Endocrinology at Boston Medical Center and an Associate Professor of Obstetrics and Gynecology at the Boston University School of Medicine
¹⁹ Professor of Medicine, New York Nutrition Obesity Research Center, Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
²⁰ Consultant endocrinologist at University Hospitals of Leicester and Honorary Associate Professor at Leicester University
²¹ Professor of Obstetrics and Gynecology at the University of Vermont and Director of the Division of Reproductive Endocrinology and Infertility. Burlington, Vermont
²² Director of Clinical Research, Hudson Institute of Medical Research; Consultant Endocrinologist, Monash Medical Centre, Melbourne, Australia
²³ Professor of Pediatrics, Professor of Genetics and Genomic Sciences, and Chief of the Adrenal Steroid Disorders Program, Icahn School of Medicine, Mount Sinai School of Medicine, New York, NY
²⁴ Professor of Medicine, Knight Cardiovascular Institute and the Division of Endocrinology, and Associate Director, Bob and Charlee Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland, OR
²⁵ Professor and Head of Department of Endocrinology, Osmania Medical College and Osmania General Hospital, Hyderabad, India.
²⁶ Professor of Pediatrics, The University of Cincinnati, Department of Pediatrics and Cincinnati Children’s Hospital Medical Center, Division of Endocrinology, Cincinnati, OH, USA
²⁷ Director of the Endocrine/Bone Disease Program, Saint Johns Cancer Institute at Saint John’s Health Center, Santa Monica, CA; Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles, CA
²⁸ Professorial Lecturer, Division of Pediatric Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York, NY. Emeritus Professor and Chair, Department of Pediatrics, University of Pittsburgh.
²⁹ CSO, ELPEN, Inc. & Director, Research Institute, Athens, Greece & Senior Investigator, Human Genetics & Precision Medicine, FORTH (ITE), Heraklion, Greece. Emeritus Scientific Director & Senior Investigator, NICHD, NIH, Bethesda, MD, USA
³⁰ Professor of Medicine, Emeritus, University of Washington, Seattle, WA
³¹ Endowed Chair, Cardiovascular Health and Risk Prevention, Pediatric Endocrinology and Diabetes, Cook Children's Medical Center, Fort Worth, TX

PMID: 25905339
Bookshelf ID: NBK279115

Excerpt

Numerous distinct pathophysiologic abnormalities have been associated with type 2 diabetes mellitus (T2DM). It is well established that decreased peripheral glucose uptake (mainly muscle) combined with augmented endogenous glucose production are characteristic features of insulin resistance. Increased lipolysis, elevated free fatty acid levels, along with accumulation of intermediary lipid metabolites contributes to further increase glucose output, reduce peripheral glucose utilization, and impair beta-cell function. Adipocyte insulin resistance and inflammation have been identified as important contributors to the development of T2DM. The presence of non-alcoholic fatty liver disease [NAFLD] is now considered an integral part of the insulin resistant state. The traditional concepts of “glucotoxicity” and lipotoxicity, which covers the process of beta cell deterioration in response to chronic elevations of glucose and lipids, has been expanded to encompass all nutrients [‘nutri-toxicity”]. The delayed transport of insulin across the microvascular system is also partially responsible for the development of tissue insulin resistance. Compensatory insulin secretion by the pancreatic beta cells may initially maintain normal plasma glucose levels, but beta cell function is already abnormal at this stage, and progressively worsens over time. Concomitantly, there is inappropriate release of glucagon from the pancreatic alpha-cells, particularly in the post-prandial period. It has been postulated that both impaired insulin and excessive glucagon secretion in T2DM are secondary to an “incretin defect”, defined primarily as inadequate release or response to the gastrointestinal incretin hormones upon meal ingestion. To a certain extent, the gut microbiome appears to play a role in the hormonal and metabolic disturbances seen in T2DM. Moreover, hypothalamic insulin resistance (central nervous system) also impairs the ability of circulating insulin to suppress glucose production, and renal tubular glucose reabsorption capacity may be enhanced, despite hyperglycemia. These pathophysiologic abnormalities should be considered for the treatment of hyperglycemia in patients with T2DM. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

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